Severe liver injury on chronic liver disease (also called chronic liver disease with severe liver injury) refers to patients with underlying chronic liver diseases who have recently suffered one or more major injuries in the liver, thus causing severe liver injury induced by acute and massive hepatocyte necrosis, which can involve important extrahepatic organs and cause multiple organ failure, including liver failure. This disease has a very high short-term mortality (40-80%) and is a severe liver disease that threatens the lives of patients. The characteristics of chronic liver disease with severe liver injury are the following: 1) the presence of chronic underlying liver disease. Chronic underlying liver disease refers to chronic hepatitis, liver fibrosis or cirrhosis induced by a variety of causes. Specific underlying liver diseases include hepatitis virus-induced chronic hepatitis, liver fibrosis or cirrhosis, chronic alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune liver disease, or drug-induced liver injury. 2) There are relatively clear and acute hepatic injury causes, including intestinal endotoxins, taking liver injury medications, alcoholism, hepatitis virus mutations, recurrence of the original hepatitis virus, infection with a new hepatitis virus, or chemical injury. 3) There is rapid deterioration of liver function within a short-term period (disease duration usually within 4 weeks), which can develop into multiple organ failure. 4) The 3-month mortality rate is greater than 40-80%.
Clinically, liver injury and severe liver injury are classified as different liver diseases. First, the pathogenesis of these 2 diseases is different. The development of acute hepatic necrosis is the key pathogenic characteristic of severe liver injury, and massive/submassive hepatic necrosis is the characteristic pathological change in liver tissues during this disease. However, liver injury involves only mild hepatic inflammation and necrosis, and there is no massive/submassive hepatic necrosis in its pathology. This is the key feature distinguishing liver injury from severe liver injury. Next, the disease outcomes differ. Liver injury will not develop into single organ or multiple organ failure and will not result in death, whereas severe liver injury patients usually progress to multiple organ failure and have a mortality rate of 40-80%. Furthermore, the clinical treatment results differ significantly. In clinical practice, many drugs can effectively prevent and treat general liver injury. For example, it has been reported that the conventional TNFα receptor with a short half-life can effectively treat or prevent liver injury; however, this agent is essentially ineffective for severe liver injury. Currently, there are no chemicals, biotech drugs, or natural drugs that can effectively prevent or treat severe liver injury on chronic liver disease. These are the fundamental reasons for the high mortality rate of this group of diseases and the short-term mortality rate of approximately 40-80%.
According to the presence of underlying liver diseases before the development of the disease, severe liver injury is divided into acute severe liver injury and severe liver injury on chronic liver disease. Severe liver injury that occurs in a healthy liver is called acute severe liver injury (also known as acute liver failure) whereas acute liver injury that occurs during chronic liver disease is called severe liver injury on chronic liver disease (also known as acute-on-chronic liver failure).
Acute severe liver injury occurs in healthy livers. After acute and massive hepatocyte necrosis, healthy livers have a very strong regenerative ability. With the help of anti-hepatic necrosis drugs, liver cells can rapidly regenerate to restore the liver function to the lowest level necessary for the basic requirements of body operation, thus improving the mortality rate. Severe liver injury on chronic liver disease occurs in livers with chronic hepatitis, fibrosis, or cirrhosis. Livers with chronic lesions are more susceptible to acute hepatocyte necrosis after liver injury than are healthy livers. In addition, because of local blood circulation disorders in liver tissues and the poor quality of residual liver cells caused by underlying diseases, livers with chronic liver disease cannot rapidly regenerate after acute and massive hepatic necrosis; thus, the diseased liver cannot bear the basic operational demands of the body within a short time period, resulting in patient death.
Therefore, significant liver degeneration defects and being prone to acute hepatic necrosis are two important differences between severe liver injury on chronic liver disease and acute severe liver injury; consequently, they are classified as two different groups of diseases in clinical situations. They have different diagnostic and therapeutic methods. In addition, drugs that are effective for acute severe liver injury are ineffective for severe liver injury on chronic liver disease.
The conventional soluble TNFα receptor can relieve liver injury caused by mild hepatocyte necrosis to some extent. However, it cannot effectively reduce acute severe liver injury or severe liver injury on chronic liver disease caused by large areas of hepatocyte necrosis. In addition, researchers in this field still cannot understand the reason for the unsatisfactory results. Therefore, it is currently difficult to practically apply the soluble TNFα receptor in the clinical treatment of severe liver injury.
In summary, there is an urgent need to identify why the TNFα receptor shows poor efficacy for the treatment of severe liver injury on chronic liver disease to further improve TNFα receptor treatment and to use this agent to effectively and rapidly prevent the development of severe liver injury on chronic liver disease. Therefore, the TNFα receptor can become an excellent drug for the prevention and treatment of severe liver injury on chronic liver disease (acute-on-chronic liver failure) in clinical situations.